Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Psychosis and Cognitive Studies Section, Clinical and Translational Neuroscience Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.
Cereb Cortex. 2019 Dec 17;29(11):4654-4661. doi: 10.1093/cercor/bhy344.
A single-nucleotide polymorphism in the promoter region of the Matrix Metalloproteinase-9 (MMP9) gene, rs3918242, has been shown to affect MMP9 expression in macrophages and was associated with schizophrenia by two independent groups. However, rs3918242's effects on MMP9 expression were not replicable in cell lines or brain tissue. Additionally, publically available data indicate that rs3918242 genotype is related not to MMP9 expression, but rather to expression of SLC12A5, a nearby gene coding for a K+/Cl- cotransporter, whose expression has also been related to schizophrenia. Here, we studied brain structure and function in healthy participants stratified by rs3918242 genotype using structural MRI (N = 298), functional MRI during an N-back working memory task (N = 554), and magnetoencephalography (MEG) during the same task (N = 190). We found rs3918242 was associated with gray matter volume (GMV) in the insula and dorsolateral prefrontal cortex bilaterally, closely replicated in discovery and replication samples; and with inferior parietal lobule (IPL) GMV when the samples were meta-analytically combined. Additionally, using both fMRI and MEG, rs3918242 was associated with right IPL working memory-related activation, replicated in two cohorts and across imaging modalities. These convergent results provide further impetus for examinations of the relationship of SLC12A5 with brain structure and function in neuropsychiatric disease.
基质金属蛋白酶 9（MMP9）基因启动子区域的单核苷酸多态性 rs3918242 已被证明会影响巨噬细胞中 MMP9 的表达，并且有两个独立的研究小组表明它与精神分裂症有关。然而，rs3918242 对 MMP9 表达的影响在细胞系或脑组织中无法复制。此外，公开可用的数据表明，rs3918242 基因型与 MMP9 的表达无关，而是与附近基因 SLC12A5 的表达有关，SLC12A5 编码一种 K+/Cl-共转运体，其表达也与精神分裂症有关。在这里，我们使用结构磁共振成像（N=298）、N 回工作记忆任务期间的功能磁共振成像（N=554）和相同任务期间的脑磁图（MEG，N=190）对按 rs3918242 基因型分层的健康参与者的大脑结构和功能进行了研究。我们发现 rs3918242 与双侧岛叶和背外侧前额叶皮质的灰质体积（GMV）有关，在发现和复制样本中得到了密切的复制；当样本进行荟萃分析时，与下顶叶（IPL）GMV 有关。此外，使用 fMRI 和 MEG，rs3918242 与 IPL 工作记忆相关的右半球激活有关，在两个队列和两种成像方式中都得到了复制。这些一致的结果为进一步研究 SLC12A5 与神经精神疾病中大脑结构和功能的关系提供了更多动力。
